This application proposes to conduct a phase II randomized, double blind, placebo-controlled trial of Iofexidine to prevent stress related opiate relapse in naltrexone treated opioid addicted individuals. Stress is known to increase drug craving and risk of relapse to drugs. Lofexidine, an alpha-2-adrenergic agonist, has been shown to attenuate stress-induced reinstatement of opiate seeking behavior in heroin dependent laboratory animals. In a recently completed 8-week pilot safety and efficacy study with 25 opioid dependent individuals seeking naltrexone (Ntx), we found the combination of Iofexidine (Lof) and naltrexone (Ntx) to be well tolerated. Individuals receiving naltrexone-lofexidine (Lof/Ntx) were significantly more likely to stay abstinent from opiates and were significantly more compliant with naltrexone treatment as compared to naltrexone-placebo (Pla/Ntx) subjects. In light of these promising preliminary data, we propose a 4-year clinical trial that will recruit 120 opioid dependent individuals immediately following opioid detoxification to participate in a randomized, double blind, placebo-controlled 12-week treatment study. The following specific aims will be addressed: (1) To evaluate the safety of Iofexidine in combination with naltrexone treatment in opioid dependent individuals. ) To evaluate the efficacy of Iofexidine in enhancing naltrexone treatment in opioid dependent individuals on measures of (a) protracted opioid withdrawal symptoms; (b) opiate abstinence, and (c) naltrexone treatment adherence. (3) To assess naltrexone treatment outcomes at 1- and 3-month follow-up after 12-week Iofexidine/placebo treatment. 4) To examine whether individual differences in perceived stress and frequency and magnitude of stressful life events predicts Iofexidine treatment response and vulnerability to opiate relapse. Findings from this study will provide important information on whether pharmacologically targeting stress enhances naltrexone treatment, and whether the combination provides an efficacious opiate relapse prevention intervention.